Emphysema is a major medical problem in the US and worldwide. In this grant application we propose to develop non-invasive lung morphometry as an improved diagnostic of this debilitating disease. Our technique is based on diffusion MRI with hyperpolarized 3He gas and allows in vivo 3D tomographic estimation of the lung alveolar surface area, alveolar density, and acinar airway radii - parameters that have been used by lung physiologists for decades as the gold standard for quantifying emphysema but were previously only measurable through invasive lung biopsy. As part of the previous grant period, we obtained in vivo lung morphometry data on 30 subjects with known smoking histories in the early stages of emphysema. This data revealed very specific changes in lung morphometry which were not appreciated with conventional clinical tests, suggesting that our technique is a very sensitive tool for detecting early changes in the lung microstructure. The main goal of this Renewal Application is to extend the diagnostic potential of the in vivo lung morphometry technique for identifying structural changes in lung parenchyma to all stages of emphysema. To achieve this goal we will: (i) extend our current mathematical model of gas diffusion in lungs by incorporating the effects of progressive lung tissue destruction on 3He gas diffusion; (ii) non-invasively establish the baseline parameters of lung microstructure in healthy human subjects without smoking histories over a range of age categories; (iii) non-invasively characterize the changes in lung microstructure for subjects in the initial through advanced stages of emphysema; (iv) validate our technique against direct morphometric measurements. Overall, we propose to further develop and validate our advanced MRI techniques for imaging of the human lung as superior, specific characterization of emphysematous changes in lung, and apply these techniques to advance our understanding of the microstructural changes that occur in emphysema, across a wide range of age and disease stages. A comprehensive picture of the changes in lung microstructure at the alveolar level with emphysema progression will be elucidated, from the initial onset of alveolar deformation to the advanced stages, characterized by a dramatic loss of lung function. Our novel methods are sufficiently sensitive to allow early detection and diagnosis of emphysema, providing an opportunity to improve patient treatment outcomes, and have the potential to provide safe and non-invasive in vivo biomarkers for monitoring drug efficacy in clinical trials.